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Rectal Cancer Treatment

General Information About Rectal Cancer

Incidence and Mortality

Estimated new cases and deaths from rectal cancer in the United States in 2013:[1]

New cases: 40,340 (rectal cancer only).

Deaths: 50,830 (colon and rectal cancers combined).

It is difficult to separate epidemiological considerations of rectal cancer from those of colon cancer because epidemiological studies often consider colon and rectal cancer (i.e., colorectal cancer) together.

Epidemiology

Worldwide, colorectal cancer is the third most common form of cancer. In 2000, colorectal cancer accounted for 9.4% of the world's new cancers, with 945,000 cases diagnosed, and 7.9% of the world's cancer deaths, with 492,000 deaths.[2] Colorectal cancer affects men and women almost equally. Among all racial groups in the United States, African Americans have the highest sporadic colorectal cancer incidence and mortality rates.[3,4]

Adenocarcinomas account for the vast majority of rectal tumors in the United States.[5] Rare tumors, including carcinoid tumors, lymphomas, and neuroendocrine tumors, account for less than 3% of colorectal tumors.[5]

Gastrointestinal stromal tumors can occur in the rectum. (Refer to the PDQ summary on Gastrointestinal Stromal Tumors Treatment for more information.)

Anatomy

The rectum is located within the pelvis, extending from the transitional mucosa of the anal dentate line to the sigmoid colon at the peritoneal reflection; by rigid sigmoidoscopy, the rectum measures between 10 cm and 15 cm from the anal verge.[6] The location of a rectal tumor is usually indicated by the distance between the anal verge, dentate line, or anorectal ring and the lower edge of the tumor, with measurements differing depending on the use of a rigid or flexible endoscope or digital examination.[7] The distance of the tumor from the anal sphincter musculature has implications for the ability to perform sphincter-sparing surgery. The bony constraints of the pelvis limit surgical access to the rectum, which results in a lesser likelihood of attaining widely negative margins and a higher risk of local recurrence.[6]

Risk Factors

Genetic risk factors

Individuals with certain known single-gene disorders are at an increased risk of developing rectal cancer. Single-gene disorders related to known syndromes account for about 10% to 15% of colorectal cancers. (Refer to the PDQ summary on Genetics of Colorectal Cancer for more information.) The hereditary colorectal cancer syndromes and some genes that are involved include:[7,8,9]

HNPCC, the result of defects in MMR genes (involving hMSH2, hMLH1, hPMS1, hPMS2, or hMSH6) represents the most common form of hereditary colorectal cancer, accounting for approximately 3% to 5% of all colorectal malignancies.[8] The majority of genetically defined cases involve hMSH2 on chromosome 2p, and hMLH1 on chromosome 3p. In affected families, 15% to 60% of family members are found to have mutations in hMSH2 or hMLH1; the mutation prevalence depends on features of the family history.[10] Ashkenazi Jews also have an increased risk for colorectal cancer related to a mutation in the APC gene (I1307K), which occurs in 6% to 7% of the Ashkenazi Jewish population.[11]

Other risk factors

More common conditions with an increased risk include:

Personal history of colorectal cancer or colorectal adenomas.

First-degree family history of colorectal cancer or colorectal adenomas.[12]

These high-risk groups account for only 23% of all colorectal cancers. Limiting screening or early cancer detection to only these high-risk groups would miss the majority of colorectal cancers.[15] (Refer to the PDQ summaries on Colorectal Cancer Screening and Colorectal Cancer Prevention for more information.)

Clinical Presentation and Symptoms

Similar to colon cancer, symptoms of rectal cancer may include the following:[16]

Gastrointestinal bleeding.

Change in bowel habits.

Abdominal pain.

Intestinal obstruction.

Weight loss.

Change in appetite.

Weakness.

Excepting obstructive symptoms, the symptoms of rectal cancer neither necessarily correlate with the stage of disease nor signify a particular diagnosis.[17] Physical examination may reveal a palpable mass and bright blood in the rectum. With metastatic disease, adenopathy, hepatomegaly, or pulmonary signs may be present.[7] Laboratory examination may reveal iron-deficiency anemia and electrolyte and liver function abnormalities.

Clinical Evaluation and Staging

Accurate staging provides crucial information about the location and size of the primary tumor in the rectum, and, if present, the size, number, and location of any metastases. Accurate initial staging can influence therapy by helping to determine the type of surgical intervention and the choice of neoadjuvant therapy to maximize the likelihood of resection with clear margins. In primary rectal cancer, pelvic imaging helps determine the depth of tumor invasion, the distance from the sphincter complex, the potential for achieving negative circumferential (radial) margins, and the involvement of locoregional lymph nodes or adjacent organs.[18] The initial clinical evaluation and staging procedures may include the following:[7,18,19,20,21,22,23]

Magnetic resonance imaging (MRI) of the abdomen and pelvis to determine the depth of penetration and the potential for achieving negative circumferential (radial) margins, as well as to identify locoregional nodal metastases and distant metastatic disease.[18]

Endorectal ultrasound (ERUS) with a rigid probe or a flexible scope for stenotic lesions to determine the depth of penetration and identify locoregional nodal metastases.[19,21]

Measurement of the serum carcinoembryonic antigen (CEA) level for prognostic assessment and the determination of response to therapy.[22,23]

In the tumor (T) staging of rectal carcinoma, several studies indicate that the accuracy of ERUS ranges from 80% to 95% compared with 65% to 75% for CT and 75% to 85% for MRI. The accuracy in determining metastatic nodal involvement by ERUS is approximately 70% to 75% compared with 55% to 65% for CT and 60% to 70% for MRI.[19] In a meta-analysis of 84 studies, none of the three imaging modalities, including ERUS, CT, and MRI, were found to be significantly superior to the others in staging nodal status.[24] ERUS using a rigid probe may be similarly accurate in T and regional lymph node (N) staging when compared to ERUS using a flexible scope; however, a technically difficult ERUS may give an inconclusive or inaccurate result for both T stage and N stage. In this case, further assessment by MRI or flexible ERUS may be considered.[21,25]

In patients with rectal cancer, the circumferential resection margin (CRM) is an important pathological staging parameter. Measured in millimeters, it is defined as the retroperitoneal or peritoneal adventitial soft-tissue margin closest to the deepest penetration of tumor.[26]

Although based on retrospective data, the American Joint Committee on Cancer and a National Cancer Institute-sponsored panel have recommended that at least 12 lymph nodes be examined in patients with colon and rectal cancer to confirm the absence of nodal involvement by the tumor.[7,26,27,28][Level of evidence: 3iiiA] This recommendation takes into consideration that the number of lymph nodes examined is a reflection of both the aggressiveness of lymphovascular mesenteric dissection at the time of surgical resection and the pathologic identification of nodes in the specimen. Retrospective studies have demonstrated that the number of lymph nodes examined in colon and rectal surgery may be associated with therapeutic outcome.[29,30,31,32] Staging studies may be required if recurrence or progression of disease is suspected; MRI may be particularly helpful in determining sacral involvement in local recurrence.[18]

Treatment

Because of the increased risk of local recurrence and a poorer overall prognosis, the management of rectal cancer varies somewhat from that of colon cancer. Differences include surgical technique, the use of radiation therapy, and the method of chemotherapy administration. In addition to determining the intent of rectal cancer surgery (i.e., curative or palliative), it is important to consider therapeutic issues related to the maintenance or restoration of normal anal sphincter, genitourinary, and sexual functions.[25,33] The approach to the management of rectal cancer should be multimodal and should involve a multidisciplinary team of cancer specialists with expertise in gastroenterology, medical oncology, surgical oncology, radiation oncology, and radiology.

The surgical approach to treatment varies according to the location, stage, and presence or absence of high-risk features (i.e., positive margins, lymphovascular invasion, perineural invasion, and poorly differentiated histology) and may include:[25,33,34]

TME via abdominoperineal resection (APR) for patients who are not candidates for sphincter-preserving operations, leaving patients with a permanent end-colostomy.

Polypectomy alone for cure may be used in certain instances in which polyps with invasive cancer can be completely resected with clear margins and have favorable histologic features.[35,36] For patients with advanced cancers of the mid- to upper rectum, LAR followed by the creation of a colorectal anastomosis may be the treatment of choice. However, in general, for locally advanced rectal cancers for which radical resection is indicated, TME with ANP techniques via LAR is preferable to APR.[25,33]

Although postoperative therapy for patients with stage II or III rectal cancer remains an acceptable option, neoadjuvant therapy for rectal cancer, using preoperative chemoradiation, is now the preferred option for patients with stage II and III disease.[37][Level of evidence: 1iA] Benefits of neoadjuvant chemoradiation include tumor regression, downstaging and improvement in resectability, and a higher rate of sphincter preservation and local control.[37] Complete pathologic response rates of 10% to 25% may be achieved with preoperative chemoradiation therapy.[38,39,40,41,42,43,44,45] However, preoperative radiation therapy is associated with increased complications compared to surgery alone; some patients with cancers at a lower risk of local recurrence might be adequately treated with surgery and adjuvant chemotherapy.[46,47,48,49] (See Treatment Option Overview section for more information.)

Prognostic Factors

The prognosis of patients with rectal cancer is related to several factors, including the following:[7,25,26,29,30,31,32,50,51,52]

Presence or absence of nodal involvement and the number of positive lymph nodes.[7,29,30,31,32]

CRM or depth of penetration of the tumor through the bowel wall.[7,25,54]

However, only disease stage (tumor, nodal, and distant) has been validated in multi-institutional prospective studies.

A large number of studies have evaluated various other clinical, pathologic, and molecular parameters; as yet, none has been validated in multi-institutional prospective trials.[55,56,57,58,59,60,61] For example, MSI-H, also associated with hereditary nonpolyposis rectal cancer, was shown to be associated with improved survival independent of tumor stage in a population-based series of 607 patients with colorectal cancer who were 50 years old or younger at the time of diagnosis.[62] In addition, gene expression profiling has been reported to be useful in predicting the response of rectal adenocarcinomas to preoperative chemoradiation therapy and in determining the prognosis of stage II and III rectal cancer after neoadjuvant 5-fluorouracil-based chemoradiation therapy.[63,64] Racial and ethnic differences in overall survival (OS) after adjuvant therapy for rectal cancer have been observed, with shorter OS for blacks compared to whites; factors contributing to this disparity may include tumor position, type of surgical procedure, and various comorbid conditions.[65]

Follow-up

The primary goals of postoperative surveillance programs for rectal cancer are the following:[66]

1.

To assess the efficacy of initial therapy.

2.

To detect new or metachronous malignancies.

3.

To detect potentially curable recurrent or metastatic cancers.

Routine, periodic studies following patients treated for rectal cancer may lead to earlier identification and management of recurrent disease.[66,67,68,69,70] A statistically significant survival benefit has been demonstrated for more intensive follow-up protocols in two clinical trials. A meta-analysis that combined these two trials with four others was reported to show a statistically significant improvement in survival for patients who were intensively followed.[66,71,72] Guidelines for surveillance after initial treatment with curative intent for colorectal cancer vary between leading U.S. and European societies, and optimal surveillance strategies remain uncertain.[73,74] Large, well-designed, prospective, multi-institutional, randomized studies may be required to establish an evidence-based consensus for follow-up evaluation.

Measurement of CEA, a serum glycoprotein, is frequently used in the management and follow-up of patients with rectal cancer. A review of the use of this tumor marker for rectal cancer suggests the following:[66]

Serum CEA testing is not a valuable screening tool for rectal cancer because of its low sensitivity and low specificity.

Postoperative CEA testing should be restricted to patients who are potential candidates for further intervention, as follows:

1.

Patients with stage II or III rectal cancer (every 2 to 3 months for at least 2 years after diagnosis).

2.

Patients with rectal cancer who would be candidates for resection of liver metastases.

In one retrospective study of the Dutch TME trial for the treatment of rectal cancer, investigators found that the preoperative serum CEA level was normal in the majority of patients with rectal cancer, and yet, serum CEA levels rose by at least 50% in patients with recurrence; the authors concluded that serial, postoperative CEA testing cannot be discarded based on a normal preoperative serum CEA level in patients with rectal cancer.[75,76]

Related Summaries

Other PDQ summaries containing information related to rectal cancer include the following:

Stage Information for Rectal Cancer

Treatment decisions should be made with reference to the TNM classification system,[1] rather than the older Dukes or the Modified Astler-Coller classification schema.

The American Joint Committee on Cancer (AJCC) and a National Cancer Institute-sponsored panel recommended that at least 12 lymph nodes be examined in patients with colon and rectal cancer to confirm the absence of nodal involvement by the tumor.[2,3,4] This recommendation takes into consideration that the number of lymph nodes examined is a reflection of both the aggressiveness of lymphovascular mesenteric dissection at the time of surgical resection and the pathologic identification of nodes in the specimen. Retrospective studies, such as Intergroup trial INT-0089 [EST-2288], have demonstrated that the number of lymph nodes examined in colon and rectal surgery may be associated with patient outcome.[5,6,7,8]

Table 1. Primary Tumora

b Tis includes cancer cells confined within the glandular basement membrane (intraepithelial) or mucosal lamina propria (intramucosal) with no extension through the muscularis mucosae into the submucosa.

c Direct invasion in T4 includes invasion of other organs or other segments of the colorectum as a result of direct extension through the serosa, as confirmed on microscopic examination (e.g., invasion of the sigmoid colon by a carcinoma of the cecum) or, for cancers in a retroperitoneal or subperitoneal location, direct invasion of other organs or structures by virtue of extension beyond the muscularis propria (i.e., respectively, a tumor on the posterior wall of the descending colon invading the left kidney or lateral abdominal wall; or a mid or distal rectal cancer with invasion of prostate, seminal vesicles, cervix, or vagina).

d Tumor that is adherent to other organs or structures, grossly, is classified cT4b. However, if no tumor is present in the adhesion, microscopically, the classification should be pT1–4a depending on the anatomical depth of wall invasion. The V and L classifications should be used to identify the presence or absence of vascular or lymphatic invasion, whereas the PN site-specific factor should be used for perineural invasion.

TX

Primary tumor cannot be assessed.

T0

No evidence of primary tumor.

Tis

Carcinomain situ: intraepithelial or invasion of lamina propria.b

T1

Tumor invades submucosa.

T2

Tumor invades muscularis propria.

T3

Tumor invades through the muscularis propria into pericolorectal tissues.

T4a

Tumor penetrates to the surface of the visceral peritoneum.c

T4b

Tumor directly invades or is adherent to other organs or structures.c,d

Table 2. Regional Lymph Nodes (N)a,b

b A satellite peritumoral nodule in the pericolorectal adipose tissue of a primary carcinoma without histologic evidence of residual lymph node in the nodule may represent discontinuous spread, venous invasion with extravascular spread (V1/2), or a totally replaced lymph node (N1/2). Replaced nodes should be counted separately as positive nodes in the N category, whereas discontinuous spread or venous invasion should be classified and counted in the site-specific factor category Tumor Deposits.

NX

Regional lymph nodes cannot be assessed.

N0

No regional lymph node metastasis.

N1

Metastases in 1–3 regional lymph nodes.

N1a

Metastasis in 1 regional lymph node.

N1b

Metastases in 2–3 regional lymph nodes.

N1c

Tumor deposit(s) in the subserosa, mesentery, or nonperitonealized pericolic or perirectal tissues without regional nodal metastases.

Table 4. Anatomic Stage/Prognostic Groupsa,b

b cTNM is the clinical classification, and pTNM is the pathologic classification. The y prefix is used for those cancers that are classified after neoadjuvant pretreatment (e.g., ypTNM). Patients who have a complete pathologic response (ypT0, N0, cM0) may be similar to stage group 0 or I. The r prefix is to be used for those cancers that have recurred after a disease-free interval (rTNM).

A major pooled analysis evaluating the impact of T and N stage and treatment on survival and relapse in patients with rectal cancer who are treated with adjuvant therapy has been published.[9] In addition, a new tumor-metastasis staging strategy for node-positive rectal cancer has been proposed.[10]

Treatment Option Overview

Primary Surgical Therapy

The primary treatment for patients with rectal cancer is surgical resection of the primary tumor. Local excision of clinical T1 tumors is an acceptable surgical technique for appropriately selected patients. For all but T1 tumors, a mesorectal excision is the treatment of choice. Very selected patients with T2 tumors may be candidates for local excision. Local failure rates in the range of 4% to 8% following rectal resection with appropriate mesorectal excision (total mesorectal excision [TME] for low/middle rectal tumors and mesorectal excision at least 5 cm below the tumor for high rectal tumors) have been reported.[1,2,3,4,5]

The low incidence of local relapse following meticulous mesorectal excision has led some investigators to question the routine use of adjuvant radiation therapy. Because of an increased tendency for first failure in locoregional sites only, the impact of perioperative radiation therapy is greater in rectal cancer than in colon cancer.[6]

Preoperative Chemoradiation Therapy

Preoperative chemoradiation therapy has become the standard of care for patients with clinically staged T3–T4 or node-positive disease, based on the results of several studies.

German Rectal Cancer Study Group

Multiple phase II studies of preoperative chemoradiation suggested that administering radiation therapy prior to surgery improved the toxicity profile of chemoradiation and enhanced the possibility of sphincter-sparing surgery. The German Rectal Cancer Study Group randomly assigned 823 patients with ultrasound (US)-staged T3–T4 or node-positive rectal cancer to either preoperative chemoradiation therapy or postoperative chemoradiation therapy (50.4 Gy in 28 daily fractions to the tumor and pelvic lymph nodes concurrent with infusional 5-fluorouracil (5-FU) 1,000 mg/m2 daily for 5 days during the first and fifth weeks of radiation therapy).[7] All patients received a TME and an additional four cycles of 5-FU–based chemotherapy postoperatively.

The overall 5-year survival rates were 76% and 74% for preoperative and postoperative chemoradiation, respectively (P = .80). The 5-year cumulative incidence of local relapse was 6% for patients assigned to preoperative chemoradiation and 13% in the postoperative treatment group (P = .006). Grade 3 or grade 4 acute toxic effects occurred in 27% of the patients in the preoperative treatment group as compared with 40% of the patients in the postoperative treatment group (P = .001); the corresponding rates of long-term toxic effects were 14% and 24%, respectively (P = .01).[7][Level of evidence: 1iA] There was no difference in the number of patients receiving an abdominoperineal resection in each arm. However, among the 194 patients with tumors that were determined by the surgeon before randomization to require an abdominoperineal excision, a statistically significant increase in sphincter preservation was achieved among patients who received preoperative chemoradiation (P = .004).

These results have now been updated with a median follow-up of 11 years.[8] The 10-year overall survival (OS) is equivalent in both arms (10-year OS, 59.6% vs. 59.9%, respectively P = .85). However, a local-control benefit persists among patients treated with preoperative chemoradiation compared with postoperative chemoradiation (10-year cumulative of local relapse, 7.1% vs. 10.1%, respectively; P = .048). There were no significant differences detected for a 10-year cumulative incidence of distant metastases or disease-free survival (DFS). Among the patients assigned to the postoperative chemoradiation treatment arm, 18% actually had pathologically determined stage I disease and were overestimated by endorectal US to have T3 or T4 or N1 disease. A similar number of patients were possibly overtreated in the preoperative treatment group.[8]

National Surgical Adjuvant Breast and Bowel Project (NSABP)

The NSABP R-03 trial similarly compared preoperative with postoperative chemoradiation therapy for patients with clinical T3 or T4 or node-positive rectal cancer. Chemotherapy consisted of fluorouracil and leucovorin with 45 Gy in 25 fractions with a 5.4 Gy boost. Although the intended sample size was 900 patients, the study closed early because of poor accrual, with 267 patients. With a median follow-up of 8.4 years, preoperative chemoradiation was found to confer a significant improvement in 5-year DFS (64.7% vs. 53.4% for postoperative patients, P = .011). Similar to the German Rectal Study, there was no significant difference seen in OS between treatment arms (74.5% vs. 65.6%, P = .065 for preoperative vs. postoperative chemoradiation).[9][Level of evidence: 1iiA]

Postoperative Chemoradiation Therapy

Recent progress in adjuvant postoperative treatment regimens relates to the integration of systemic therapy with radiation therapy, as well as redefining the techniques for both modalities. The efficacy of postoperative radiation therapy and 5-FU-based chemotherapy for stage II and III rectal cancer was established by a series of prospective, randomized clinical trials from the Gastrointestinal Tumor Study Group (GITSG-7175), the Mayo/North Central Cancer Treatment Group (NCCTG-794751), and the National Surgical Adjuvant Breast and Bowel Project (NSABP-R-01).[10,11,12][Level of evidence: 1iiA] These studies demonstrated an increase in both disease-free survival (DFS) interval and OS when radiation therapy was combined with chemotherapy after surgical resection. Following publication of the results of these trials, experts at a National Cancer Institute-sponsored Consensus Development Conference in 1990 concluded that postoperative combined-modality treatment is recommended for patients with stage II and III rectal carcinoma.[13]

Chemotherapy

Subsequent studies have attempted to increase the survival benefit by improving radiation sensitization and by identifying the optimal chemotherapeutic agents and delivery systems. The agents associated with the first successful combined-modality treatments were 5-FU and semustine. Semustine is not commercially available, and previous studies have associated this drug with the potential for increased risks of renal toxic effects and leukemia.

A follow-up randomized trial from GITSG demonstrated that semustine does not produce an additive survival benefit to radiation therapy and 5-FU.[14][Level of evidence: 1iiA] The Intergroup 86-47-51 trial (NCCTG-864751 [MAYO-864751]) showed a 10% improvement in OS with the use of continuous-infusion 5-FU (225 mg/m2 /day) throughout the course of radiation therapy when compared with bolus 5-FU (500 mg/m2 times three injections in the first and fifth weeks of radiation).[15][Level of evidence: 1iiA]

Subsequently, several studies attempted to determine the optimal way to deliver adjuvant 5-FU. The final results of Intergroup 0114 (INT-0114 [CLB-9081]) demonstrated no survival or local control benefit with the addition of leucovorin (LV), levamisole, or both to 5-FU administered postoperatively for stage II and III rectal cancers at a median follow-up of 7.4 years.[16][Level of evidence: 1iiA] Another study, Intergroup 0144 (SWOG-9304 [NCT00002551]), was a three-arm randomized trial designed to determine whether continuous-infusion 5-FU throughout the entire standard six-cycle course of adjuvant chemotherapy was more effective than continuous 5-FU only during pelvic radiation.[17]

Median follow-up was 5.7 years. Lethal toxicity was less than 1%, with grade 3 to 4 hematologic toxicity in 55% and 49% of patients in the two bolus arms, respectively (i.e., arms 1 and 3) versus 4% of patients in the continuous-infusion arm. No DFS, OS, or locoregional failure (LRF) difference was detected (across all arms: 3-year DFS, 67% to 69%; 3-year OS, 81% to 83%; LRF, 4.6% to 8%).[17][Level of evidence: 1iiA]

Addition of radiation therapy

Although the above data demonstrate a benefit with postoperative radiation therapy and 5-FU chemotherapy for patients with stage II and III rectal cancer, a follow-up study to the NSABP-R-01 trial, the NSABP-R-02 study, addressed whether the addition of radiation therapy to chemotherapy would enhance the survival advantage reported in R-01.[18][Level of evidence: 1iiA] The addition of radiation, while significantly reducing local recurrence at 5 years (8% for chemotherapy and radiation vs. 13% for chemotherapy alone, P = .02), demonstrated no significant benefit in terms of survival. The interpretation of the interaction of radiation therapy with prognostic factors, however, was challenging. Radiation appeared to improve survival among patients younger than 60 years, as well as among patients who received abdominoperineal resection. This trial has initiated discussion in the oncologic community as to the proper role of postoperative radiation therapy. Omission of radiation therapy seems premature, since locoregional recurrence remains a clinically relevant problem.

Using current surgical techniques, including TME, it may be possible to identify subsets of patients whose chance of pelvic failure is low enough to omit postoperative radiation. A trial conducted by the Dutch Colorectal Cancer Group (DUT-KWF-CKVO-9504) randomly assigned patients with resectable rectal cancers (stages I–IV) to a short course of radiation (5 Gy × 5 days) followed by TME compared with TME alone and demonstrated no difference in OS at 2 years (82% for both arms).[19][Level of evidence: 1iiA] Local recurrence rates were significantly reduced in the radiation therapy plus TME arm (2.4%) as compared with the TME only arm (8.2%, P < .001).

At present, acceptable postoperative therapy for patients with stage II or III rectal cancer not enrolled in clinical trials includes continuous-infusion 5-FU during 45 Gy to 55 Gy pelvic radiation and four cycles of adjuvant maintenance chemotherapy with bolus 5-FU with or without modulation with LV.

An analysis of patients treated with postoperative chemotherapy and radiation therapy suggests that these patients may have more chronic bowel dysfunction compared with those who undergo surgical resection alone.[20] Improved radiation planning and techniques can be used to minimize treatment-related complications. These techniques include the use of multiple pelvic fields, prone positioning, customized bowel immobilization molds (belly boards), bladder distention, visualization of the small bowel through oral contrast, and the incorporation of three-dimensional or comparative treatment planning.[21,22]

The Role of Oxaliplatin for Localized Disease

Based on the results of several studies, oxaliplatin does not appear to add any benefit in terms of primary tumor response, but it has been associated with increased acute treatment-related toxicity.

Adjuvant oxaliplatin

Oxaliplatin has significant activity when combined with 5-FU-LV in patients with metastatic colorectal cancer. In the randomized Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) study, the toxic effects and efficacy of FOLFOX4 (a 2-hour infusion of 200 mg/m2 LV, followed by a bolus of 400 mg/m2 5-FU, and then a 22-hour infusion of 600 mg/m2 5-FU on 2 consecutive days every 14 days for 12 cycles, plus a 2-hour infusion of 85 mg/m2 oxaliplatin on day 1, given simultaneously with the LV) were compared with the same 5-FU-leucovorin regimen without oxaliplatin when administered for 6 months.[23] Each arm of the trial included 1,123 patients.

Preliminary results of the study, with 37 months of follow-up, demonstrated a significant improvement in DFS at 3 years (77.8% vs. 72.9%; P = .01) in favor of FOLFOX4. When initially reported, there was no difference in OS.[24][Level of evidence: 1iiDii] Further follow-up at 6 years demonstrated that the OS for all patients (both stage II and stage III) entered into the study was not significantly different (OS = 78.5% vs. 76.0%; HR, 0.84; 95% CI, 0.71–1.00). On subset analysis, the 6-year OS in patients with stage III colon cancer was 72.9% in the patients receiving FOLFOX and 68.9% in the patients receiving 5-FU/LV (HR, 0.80; 95% CI, 0.65–0.97, P = .023).[24][Level of evidence: 1iiA] Patients treated with FOLFOX4 experienced more frequent toxic effects, consisting mainly of neutropenia (41% >grade 3) and reversible peripheral sensory neuropathy (12.4% >grade 3). These results are still preliminary, and additional information with regard to OS is anticipated. Nevertheless, these data suggest that FOLFOX4 may be a therapeutic option for patients with resected stage III colon cancer.[25]

The results of the now completed NSABP C-07 study confirmed and extended the results of the MOSAIC trial.[26] In NSABP C-07, 2,492 patients with stage II or III colon cancer were randomly assigned to receive either FLOX (2-hour intravenous infusion of 85 mg/m2 oxaliplatin on days 1, 15, and 29 of each 8-week treatment cycle, followed by a 2-hour intravenous infusion of 500 mg/m2 LV plus bolus 500 mg/m2 5-FU 1 hour after the start of the LV infusion on days 1, 8, 15, 22, 29, and 36, followed by a 2-week rest period, for a total of three cycles [24 weeks]) or the same chemotherapy without oxaliplatin (Roswell Park regimen). The 3- and 4-year DFS rates were 71.8% and 67% for the Roswell Park regimen and 76.1% and 73.2% for FLOX, respectively. The hazard ratio was 0.80 (95% confidence interval [CI], 0.69–0.93), a 20% risk reduction in favor of FLOX (P <.004).

Adjuvant chemotherapy following chemoradiation therapy and surgery

Many academic oncologists recommend that FOLFOX be considered the standard for adjuvant chemotherapy in rectal cancer. However, there are no data in rectal cancer to support this consideration. FOLFOX has become the standard arm in the latest Intergroup study evaluating adjuvant chemotherapy in rectal cancer. An Eastern Cooperative Oncology Group trial (ECOG-E5202 [NCI-2009-00562]) randomly assigned patients with stage II or III rectal cancer who have received preoperative or postoperative chemoradiation therapy to 6 months of FOLFOX with or without bevacizumab.

Oxaliplatin with chemoradiation therapy

Oxaliplatin has also been shown to have radiosensitizing properties in preclinical models;[27] and phase II studies combining this agent with fluoropyrimidine-based chemoradiation have reported pathologic complete response (pCR) rates ranging from 14% to 30%.[28,29,30,31,32] Data from multiple studies have demonstrated a correlation between rates of pCR and endpoints including distant metastasis-free survival, DFS, and OS.[33,34,35]

pCR was the primary endpoint (albeit never validated as a true surrogate of OS) in the ACCORD 12/0405-Prodige 2 trial, which randomly assigned 598 patients with clinically staged T2 or T3 or resectable T4 rectal cancer accessible to digital rectal examination to either preoperative radiation (45 Gy in 25 fractions over 5 weeks) with capecitabine (800 mg/m2 twice daily five of every 7 days) or to a higher dose of radiation (50 Gy in 25 fractions over 5 weeks) with the same dose of capecitabine and oxaliplatin (50 mg/m2 weekly).[36] TME was performed in 98% of both groups at a median interval of 6 weeks after chemoradiation was completed. Although a higher percentage of patients achieved a pCR in the oxaliplatin-treated group (19.2% vs. 13.9%), the difference did not reach statistical significance (P = .09). Moreover, the rate of grade 3 or 4 toxicity was significantly higher in the oxaliplatin-treated group (25% vs. 11%, P < .001), and there was no difference in sphincter-sparing surgery (75% vs. 78%). Therefore, there is no current role for off-trial use of concurrent oxaliplatin and radiation in the treatment of patients with rectal cancer.

The STAR-01 trial similarly investigated the role of oxaliplatin combined with 5-FU chemoradiation for locally advanced rectal cancer.[37] This Italian study randomly assigned 747 patients with resectable, locally advanced, clinically staged T3 or T4 and/or clinical N1 to N2 adenocarcinoma of the mid- to low-rectum to receive either continuous-infusion 5-FU with radiation or to receive the same regimen in combination with oxaliplatin (60 mg/m2). Although the primary endpoint was OS, a protocol-planned analysis of response to preoperative therapy has been preliminarily reported. The rate of pCR was equivalent at 16% in both arms (OR 0.98; 95% CI, 0.66–1.44, P = .904). Additionally, there was no difference noted in the rate of pathologically positive lymph nodes, tumor infiltration beyond the muscularis propria, or the rate of circumferential margin positivity. Again, an increase in grades 3 to 4 treatment-related acute toxicity was noted with the addition of oxaliplatin (24% vs. 8%, P <.001). Longer-term outcomes including OS have not yet been reported.[37][Level of evidence: 1iiA]

The NSABP-R-04 trial randomly assigned 1,608 patients with clinically staged T3 or T4 or clinical node-positive adenocarcinoma within 12 cm of the anal verge in a 2 × 2 factorial design to one of the following four treatment groups:

1.

Intravenous continuous infusion (IVCI) 5-FU with radiation therapy.

2.

Capecitabine with radiation therapy.

3.

IVCI 5-FU plus weekly oxaliplatin with radiation therapy.

4.

Capecitabine plus weekly oxaliplatin with radiation therapy.

The primary objective of this study is locoregional disease control.

Preliminary results, reported in abstract form at the 2011 American Society of Clinical Oncology annual meeting, demonstrated that there was no significant difference in the rates of pCR, sphincter-sparing surgery, or surgical downstaging between the 5-FU and capecitabine regimens or between the regimens with and without oxaliplatin. However, similar to the other studies, patients treated with oxaliplatin had significantly higher rates of grade 3 and 4 acute toxicity (15.4% vs. 6.6%, P < .001).[38][Level of evidence: 1iiD]

The German CAO/ARO/AIO-04 trial randomly assigned 1,236 patients with clinically staged T3 to T4 or clinical node-positive adenocarcinoma within 12 cm from the anal verge to receive either concurrent chemoradiation with 5-FU (week 1 and week 5) or concurrent chemoradiation with 5-FU daily (250 mg/m2) and oxaliplatin (50 mg/m2).[39] In contrast to the previous studies, a significantly higher rate of pCR was achieved in patients who received oxaliplatin (17% vs. 13%, P = .038). There was no significant difference in rates of overall grades 3 and 4 toxicity, however, diarrhea and nausea and vomiting were more common among those treated with oxaliplatin. The 5-FU schedules in this study differed between the two arms, which may have contributed to the difference in outcomes noted. Longer follow-up will be necessary to determine the effect on the primary endpoint of the study, DFS.[39][Level of evidence: 1iiD]

Treatment Toxicity

The acute side effects of pelvic radiation therapy for rectal cancer are mainly the result of gastrointestinal toxicity, are self-limiting, and usually resolve within 4 to 6 weeks of completing treatment. Of greater concern is the potential for late morbidity following rectal cancer treatment. Patients who undergo aggressive surgical procedures for rectal cancer can have chronic symptoms, particularly if there is impairment of the anal sphincter.[40] Patients treated with adjuvant radiation therapy appear to have increased chronic bowel dysfunction, anorectal sphincter dysfunction (if the sphincter was surgically preserved), and sexual dysfunction than those who undergo surgical resection alone.[41,42,43,44,45,46,47]

A Cochrane review highlights the risks of increased surgical morbidity as well as late rectal and sexual function in association with adjuvant therapy.[40] Improved radiation planning and techniques may minimize these acute and late treatment-related complications. These techniques include:[48,49,50]

The use of high-energy radiation machines.

The use of multiple pelvic fields.

Prone patient positioning.

Customized patient molds (belly boards) to exclude as much small bowel as possible from the fields and immobilize patients during treatment.

Bladder distention during radiation therapy to exclude as much small bowel as possible from the fields.

Visualization of the small bowel through oral contrast during treatment planning so that when possible, the small bowel can be excluded from the radiation field.

The use of three dimensional or other advanced radiation planning techniques.

In Europe, it is common to deliver preoperative radiation therapy alone in one week (5 Gy x 5 daily treatments) followed by surgery one week later, as compared to the long-course chemoradiation approach in the United States. One reason for this difference is the concern in the U.S. for heightened late effects with high radiation doses per fraction.

A Polish study randomly assigned 316 patients between preoperative long course chemoradiation (50.4 Gy in 28 daily fractions with 5-FU and LV) and short-course preoperative radiation therapy (25 Gy in 5 fractions).[47] Although the primary endpoint was sphincter preservation, late toxicity was not statistically significantly different between the two treatment approaches (7% long course vs. 10% short course). Of note, data on anal sphincter and sexual function were not reported, and toxicity was physician determined, not patient reported.

Ongoing clinical trials comparing preoperative and postoperative adjuvant chemoradiation therapy should further clarify the impact of either approach on bowel function and other important quality-of-life issues (e.g., sphincter preservation) in addition to the more conventional endpoints of DFS and OS.

Radiation therapy and fluorouracil with or without semustine for the treatment of patients with surgical adjuvant adenocarcinoma of the rectum. Gastrointestinal Tumor Study Group. J Clin Oncol 10 (4): 549-57, 1992.

Stage 0 Rectal Cancer

Stage 0 rectal cancer is the most superficial of all rectal lesions and is limited to the mucosa without invasion of the lamina propria. Because of its superficial nature, surgical and other procedures may be limited.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage 0 rectal cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Local transanal or other resection [1,2] with or without perioperative external-beam radiation therapy (EBRT) plus fluorouracil (5-FU).

There are three potential options for surgical resection in stage I rectal cancer: local excision, LAR, and APR. Local excision should be restricted to tumors confined to the rectal wall and that do not, on rectal ultrasound or magnetic resonance imaging, involve the full thickness of the rectum (i.e., not a T3 tumor). The ideal candidate for local excision has a T1 tumor with well-to-moderate differentiation that occupies less than one-third of the circumference of the bowel wall. Local excision should only be applied to very select patients with T2 tumors, as there is a higher risk of local and systemic failure.

For patients with T1 and T2 tumors, no randomized trials are available to compare local excision with or without postoperative chemoradiation to wide surgical resection (LAR and APR). Investigators with the Cancer and Leukemia Group B (CALGB) enrolled patients with T1 and T2 rectal adenocarcinomas that were within 10 cm of the dentate line and not more than 4 cm in diameter, and involving not more than 40% of the rectal circumference, onto a prospective protocol, CLB-8984. Patients with T1 tumors received no additional treatment following surgery, whereas patients with T2 tumors were treated with EBRT (54 Gy of 30 fractions, 5 days/week) and 5-FU (500 mg/m2 on days 1 through 2 and days 29 through 31 of radiation). At 48 months median follow-up, the 6-year failure-free survival and overall survival (OS) rates for patients with T1 tumors were 83% and 87%, respectively. For patients with T2 tumors, the 6-year failure-free survival and OS rates were 71% and 85%, respectively.[3]

Patients with tumors that are pathologically T1 may not need postoperative therapy. Patients with tumors that are T2 or greater have lymph node involvement about 20% of the time, and additional therapy should be considered, such as radiation and chemotherapy, or more standard surgical resection.[4] Patients with poor histologic features or positive margins after local excision should consider LAR or APR and postoperative treatment as dictated by full surgical staging.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I rectal cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Postoperative chemoradiation for patients with stage II or III rectal cancer who did not receive preoperative chemoradiation.

4.

Four to six months of 5-FU-based chemotherapy postoperatively.

5.

A clinical trial.

Prior to the standard use of preoperative chemoradiation for stage II and III rectal cancer, several studies established the benefits of adjuvant combined-modality therapy for surgical stage II and III disease. Intergroup protocol 86-47-51 (MAYO-864751) demonstrated a 10% improvement in overall survival (OS) with the use of continuous-infusion 5-FU (225 mg/m2 /day throughout the entire course of radiation therapy) compared with bolus 5-FU (500 mg/m2 /day for three consecutive days during the first and fifth weeks of radiation).[1][Level of evidence: 1iiA] The final results of (CLB-9081) showed no survival or local-control benefit with the addition of leucovorin (LV), levamisole, or both to 5-FU administered postoperatively for patients with stage II and III rectal cancers at a median follow-up of 7.4 years.[2][Level of evidence: 1iiA]

Another study, (INT-0144 [NCT00002551]), was a three-arm randomized trial designed to determine whether continuous-infusion 5-FU throughout the entire standard six-cycle course of adjuvant chemotherapy was more effective than continuous 5-FU only during pelvic radiation and included the following:[3]

Median follow-up was 5.7 years. Lethal toxicity was less than 1%, with grade 3 to 4 hematologic toxicity in 55% and 49% of patients in the two bolus arms, respectively (i.e., arms 1 and 3), versus 4% of patients in the continuous-infusion arm. No DFS, OS, or locoregional failure (LRF) difference was detected (across all arms: 3-year DFS, 67% to 69%; 3-year OS, 81% to 83%; LRF, 4.6% to 8%).[3][Level of evidence: 1iiA]

The German Rectal Cancer Study Group randomly assigned 823 patients with ultrasound (US)-staged T3 orT4 or node-positive rectal cancer to either preoperative chemoradiation or postoperative chemoradiation (50.4 Gy in 28 daily fractions to the tumor and pelvic lymph nodes concurrent with infusional 5-FU 1,000 mg/m2 daily for 5 days during the first and fifth weeks of radiation therapy).[4] All patients received a TME and an additional four cycles of 5-FU-based chemotherapy. The 5-year OS rates were 76% and 74% for preoperative and postoperative chemoradiation, respectively (P = .80). The 5-year cumulative incidence of local relapse was 6% for patients assigned to preoperative chemoradiation and 13% in the postoperative-treatment group (P = .006). Grade 3 or 4 acute toxic effects occurred in 27% of the patients in the preoperative-treatment group as compared with 40% of the patients in the postoperative-treatment group (P = .001); the corresponding rates of long-term toxic effects were 14% and 24%, respectively (P = .01).[4][Level of evidence: 1iA] There was no difference in the number of patients receiving an APR in each arm. However, among the 194 patients with tumors that were determined by the surgeon before randomization to require an abdominoperineal excision, a statistically significant increase in sphincter preservation was achieved among patients who received preoperative chemoradiation (P = .004).

These results have now been updated with a median follow-up of 11 years.[4] The 10-year overall survival (OS) is equivalent in both arms (10-year OS, 59.6% vs. 59.9%, P = .85). However, a local control benefit persists among patients treated with preoperative chemoradiation compared with postoperative chemoradiation (10-year cumulative of local relapse, respectively: 7.1% vs. 10.1%, P = .048). There were no significant differences detected for 10-year cumulative incidence of distant metastases or DFS. Among the patients assigned to the postoperative chemoradiation treatment arm, 18% actually had pathologically determined stage I disease and were overestimated by endorectal US to have T3 or T4 or N1 disease. A similar number of patients were possibly overtreated in the preoperative treatment group.

The NSABP R-03 similarly compared preoperative versus postoperative chemoradiotherapy for patients with clinically staged T3 or T4 or node-positive rectal cancer. Chemotherapy consisted of 5-FU/LV with 45 Gy in 25 fractions with a 5.4 Gy boost. Although the intended sample size was 900 patients, the study closed early because of poor accrual, with 267 patients. With a median follow-up of 8.4 years, preoperative chemoradiation was found to confer a significant improvement in 5-year DFS (64.7% vs. 53.4% for postoperative patients, P = .011). Similar to the German Rectal Study, there was no significant difference seen in OS between treatment arms (74.5% vs. 65.6%, P =. 065 for preoperative vs. postoperative chemoradiation.)[5][Level of evidence: 1iiA]

Preoperative chemoradiation therapy has become the standard of care for patients with clinically staged T3 or T4 or node-positive disease, based on the results of several studies.

Retrospective studies have demonstrated that some patients with pathological T3, N0 disease treated with no further therapy after surgery have a very low risk of local and systemic recurrence.[6] In addition, a pooled analysis of 3,791 patients enrolled in clinical trials demonstrated that, for patients with T3, N0 disease, the 5-year OS rate with surgery plus chemotherapy (84%) compared favorably with the survival rates of patients treated with surgery plus radiation and bolus chemotherapy (76%) or surgery plus radiation and protracted-infusion chemotherapy (80%).[7] However, a multi-institutional retrospective analysis demonstrated that 22% of patients thought to have clinically node-negative T3 disease by ultrasound or magnetic resonance imaging were found, at the time of resection, to have positive mesorectal lymph nodes even after chemoradiation.[8]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage II rectal cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Postoperative chemoradiation for patients with stage II or III rectal cancer who did not receive preoperative chemoradiation.

4.

Four to six months of 5-FU-based chemotherapy postoperatively.

5.

A clinical trial.

Prior to the standard use of preoperative chemoradiation for stage II and III rectal cancer, several studies established the benefits of adjuvant combined-modality therapy for surgical stage II and III disease. Intergroup protocol 86-47-51 (MAYO-864751) demonstrated a 10% improvement in overall survival (OS) with the use of continuous-infusion 5-FU (225 mg/m2 /day throughout the course of radiation therapy) compared with bolus 5-FU (500 mg/m2 /day for 3 consecutive days during the first and fifth weeks of radiation).[1][Level of evidence: 1iiA] The final results of Intergroup trial 0114 (CLB-9081) showed no survival or local-control benefit with the addition of leucovorin (LV), levamisole, or both to 5-FU administered postoperatively for stage II and III rectal cancers at a median follow-up of 7.4 years.[2][Level of evidence: 1iiA]

Another study, INT-0144 (NCT00002551), was a three-arm randomized trial designed to determine whether continuous-infusion 5-FU throughout the entire standard six-cycle course of adjuvant chemotherapy was more effective than continuous 5-FU only during pelvic radiation and included the following:[3][Level of evidence: 1iiA]

Median follow-up was 5.7 years. Lethal toxicity was less than 1%, with grade 3 to 4 hematologic toxicity in 55% and 49% of patients in the two bolus arms, respectively (i.e., arms 1 and 3) versus 4% of patients in the continuous-infusion arm. No disease-free survival (DFS), OS, or locoregional failure (LRF) difference was detected (across all arms: 3-year DFS, 67% to 69%; 3-year OS, 81% to 83%; 3-year LRF, 4.6% to 8%).[3][Level of evidence: 1iiA]

The German Rectal Cancer Study Group randomly assigned 823 patients with ultrasound (US)-staged T3 or T4 or node-positive rectal cancer to either preoperative chemoradiation or postoperative chemoradiation (50.4 Gy in 28 daily fractions to the tumor and pelvic lymph nodes concurrent with infusional 5-FU 1,000 mg/m2 daily for 5 days during the first and fifth weeks of radiation therapy).[4] All patients received a TME and an additional four cycles of 5-FU-based chemotherapy. The 5-year OS rates were 76% and 74% for preoperative and postoperative chemoradiation, respectively (P = .80). The 5-year cumulative incidence of local relapse was 6% for patients assigned to preoperative chemoradiation therapy and 13% in the postoperative-treatment group (P = .006). Grade 3 or 4 acute toxic effects occurred in 27% of the patients in the preoperative-treatment group as compared with 40% of the patients in the postoperative-treatment group (P = .001); the corresponding rates of long-term toxic effects were 14% and 24%, respectively (P = .01).[4][Level of evidence: 1iA] There was no difference in the number of patients receiving an abdominoperineal resection in each arm. However, among the 194 patients with tumors that were determined by the surgeon before randomization to require an abdominoperineal excision, a statistically significant increase in sphincter preservation was achieved among patients who received preoperative chemoradiation therapy (P = .004).

These results have now been updated with a median follow-up of 11 years.[4] The 10-year OS is equivalent in both arms (10-year OS, 59.6% vs. 59.9%, P = .85). However, a local control benefit persists among patients treated with preoperative chemoradiation compared with postoperative chemoradiation (10-year cumulative of local relapse, respectively; 7.1% vs. 10.1%, P = .048). There were no significant differences detected for 10-year cumulative incidence of distant metastases or DFS. Among the patients assigned to the postoperative chemoradiation treatment arm, 18% actually had pathologically determined stage I disease and were overestimated by endorectal US to have T3 or T4 or N1 disease. A similar number of patients were possibly overtreated in the preoperative treatment group.

The NSABP R-03 similarly compared preoperative versus postoperative chemoradiotherapy for patients with clinically staged T3 or T4 or node-positive rectal cancer. Chemotherapy consisted of 5-FU/LV with 45 Gy in 25 fractions with a 5.4 Gy boost. Although the intended sample size was 900 patients, the study closed early because of poor accrual, with 267 patients. With a median follow-up of 8.4 years, preoperative chemoradiation was found to confer a significant improvement in 5-year DFS (64.7% vs. 53.4% for postoperative patients, P = .011). Similar to the German Rectal Study, there was no significant difference seen in OS between treatment arms (74.5% vs. 65.6%, P = .065 for preoperative vs. postoperative chemoradiation.)[5][Level of evidence: 1iiA]

Preoperative chemoradiation therapy has become the standard of care for patients with clinically staged T3 or T4 or node-positive disease, based on the results of several studies.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage III rectal cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Treatment of patients with recurrent or advanced colorectal cancer depends on the location of the disease. For patients with locally recurrent and/or liver-only and/or lung-only metastatic disease, surgical resection, if feasible, is the only potentially curative treatment. Hepatic metastasis may be considered to be resectable based on the following:[17,21,24,25,26,27]

Limited number of lesions.

Intrahepatic locations of lesions.

Lack of major vascular involvement.

Absent or limited extrahepatic disease.

Sufficient functional hepatic reserve.

For patients with hepatic metastasis considered to be resectable, a negative margin resection has been associated with 5-year survival rates of 25% to 40% in mostly nonrandomized studies (such as the North Central Cancer Treatment Group trial, NCCTG-934653).[28,29,30,31,32][Level of evidence: 3iiiDiv] Better surgical techniques and advances in preoperative imaging have improved patient selection for resection. In addition, multiple studies with multiagent chemotherapy have demonstrated that patients with metastatic disease isolated to the liver, which historically would be considered unresectable, can occasionally be made resectable after the administration of chemotherapy.[33]

Currently, there are seven active and approved drugs for patients with metastatic colorectal cancer:

Fluorouracil (5-FU).

Capecitabine.

Irinotecan.

Oxaliplatin.

Bevacizumab.

Cetuximab.

Panitumumab.

When 5-FU was the only active chemotherapy drug, trials in patients with locally advanced, unresectable, or metastatic disease demonstrated partial responses and prolongation of the time-to-progression (TTP) of disease,[5,34] as well as improved survival and quality of life for patients receiving chemotherapy compared with best supportive care.[35,36,37] Several trials have analyzed the activity and toxic effects of various 5-FU-leucovorin (5-FU/LV) regimens, using different doses and administration schedules, and showed essentially equivalent results with a median survival time in the 12-month range.[38] Prior to the advent of multiagent chemotherapy, two randomized studies demonstrated that capecitabine was associated with equivalent efficacy when compared with the Mayo Clinic regimen of 5-FU/LV.[39,40][Level of evidence: 1iiA]

Irinotecan (100 mg/m2) administered as a 2-hour infusion on day 1; LV (500 mg/m2) administered as a 2-hour infusion on day 1; followed by 5-FU (2,000 mg/m2) intravenous (IV) bolus via ambulatory pump administered for a period of 24 hours on a weekly basis four times a year (52 weeks).

The CAPOX regimen (capecitabine and oxaliplatin):

Capecitabine (1,000 mg/m2) twice a day on days 1 through 14 plus oxaliplatin (70 mg/m2) on days 1 and 8 every 3 weeks.

The Douillard regimen (folic acid, 5-FU, and irinotecan):

Irinotecan (180 mg/m2) administered as a 2-hour infusion on day 1; LV (200 mg/m2) administered as a 2-hour infusion on day 1 and day 2; followed by a loading dose of 5-FU (400 mg/m2) IV bolus, then 5-FU (600 mg/m2) via ambulatory pump administered for a period of 22 hours on day 1 and day 2 every 2 weeks.

The FOLFOX4 regimen (oxaliplatin, LV, and 5-FU):

Oxaliplatin (85 mg/m2) administered as a 2-hour infusion on day 1; LV (200 mg/m2) administered as a 2-hour infusion on day 1 and day 2; followed by a loading dose of 5-FU (400 mg/m2) IV bolus, then 5-FU (600 mg/m2) administered via ambulatory pump for a period of 22 hours on day 1 and day 2 every 2 weeks.

The FOLFOX6 regimen (oxaliplatin, LV, and 5-FU):

Oxaliplatin (85–100 mg/m2) administered as a 2-hour infusion on day 1; LV (400 mg/m2) administered as a 2-hour infusion on day 1; followed by a loading dose of 5-FU (400 mg/m2) IV bolus on day 1, then 5-FU (2,400–3,000 mg/m2) administered via ambulatory pump for a period of 46 hours every 2 weeks.

The FOLFIRI regimen (LV, 5-FU, and irinotecan):

Irinotecan (180 mg/m2) administered as a 2-hour infusion on day 1; LV (400 mg/m2) administered as a 2-hour infusion on day 1; followed by a loading dose of 5-FU (400 mg/m2) IV bolus administered on day 1, then 5-FU (2,400–3,000 mg/m2) administered via ambulatory pump for a period of 46 hours every 2 weeks.

Oral capecitabine (1,000 mg/m2) twice a day for 14 days plus oxaliplatin (130 mg/m2) on day 1 every 3 weeks.

First-line multiagent chemotherapy

Three randomized studies in patients with metastatic colorectal cancer demonstrated improved response rates, progression-free survival (PFS), and OS when irinotecan or oxaliplatin was combined with 5-FU/LV.[41,42,43] An intergroup study (NCCTG-N9741) then compared IFL with FOLFOX4 in first-line treatment for patients with metastatic colorectal cancer. Patients assigned to FOLFOX4 experienced improved PFS (median, 6.9 months vs. 8.7 months; P = .014; hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.61–0.89) and OS (15.0 months vs. 19.5 months, P = .001; HR, 0.66; 95% CI, 0.54–0.82) compared with patients randomly assigned to IFL.[Level of evidence: 1iiA] Subsequently, two studies compared FOLFOX with FOLFIRI, and patients were allowed to cross over after progression on first-line therapy, respectively.[44,45][Level of evidence: 1iiDiii] PFS and OS were identical between the treatment arms in both studies. Since the publication of these studies, the use of either FOLFOX or FOLFIRI is considered acceptable for first-line treatment of patients with metastatic colorectal cancer.

The Bolus, Infusional, or Capecitabine with Camptosar-Celecoxib (BICC-C) trial evaluated several different irinotecan-based regimen in patients with previously untreated metastatic colorectal cancer: FOLFIRI, mIFL, and capecitabine/irinotecan (CAPIRI).[46] The study randomly assigned 430 patients and was closed early due to poor accrual. The patients who received FOLFIRI had a better PFS than the patients who received either mIFL (7.6 months vs. 5.9 months, P = .004) or CAPIRI (7.6 months vs. 5.8 months, P = .015). Patients who received CAPIRI had the highest (grade 3 or higher) rates of nausea, vomiting, diarrhea, dehydration, and hand-foot syndrome. After bevacizumab was approved, the BICC-C trial was amended and an additional 117 patients were randomly assigned to receive FOLFIRI/bevacizumab or mIFL/bevacizumab. Although the primary endpoint of PFS was not significantly different, patients receiving FOLFIRI/bevacizumab had a significantly better OS (28.0 months vs. 19.2 months, P = .037; HR for death, 1.79; 95% CI 1.12 to 2.88). When using an irinotecan-based regimen as first-line treatment of metastatic colorectal cancer, FOLFIRI is preferred.[46][Level of evidence: 1iiDiii] (Refer to the PDQ summary on Nausea and Vomiting and refer to the Diarrhea section in the PDQ summary on Gastrointestinal Complications for information on diarrhea and dehydration.)

Randomized phase III trials have addressed the equivalence of substituting capecitabine for infusional 5-FU. Two phase III studies have evaluated FUOX versus CAPOX.[47,48] The AIO Colorectal Study Group randomly assigned 474 patients to either FUFOX or CAPOX. The median PFS was 7.1 months for the CAPOX arm and 8.0 months for the FUFOX arm (HR, 1.17; 95% CI, 0.96–1.43: P = .117), and the HR was in the prespecified equivalence range.[48] The Spanish Cooperative Group randomly assigned 348 patients to CAPOX or FUOX.[47] The TTP was 8.9 months versus 9.5 months (P = .153) and met the prespecified range for noninferiority.[47][Level of evidence: 1iiDiii] When using an oxaliplatin-based regimen as first-line treatment of metastatic colorectal cancer, a CAPOX regimen is not inferior to a FUOX regimen.

Despite the lack of direct data, in standard practice, bevacizumab was added to FOLFOX as a standard first-line regimen based on the results of NCCTG-N9741.[50] Subsequently, in a randomized phase III study, patients with untreated, stage IV colorectal cancer were randomly assigned in a 2 × 2 factorial design to CAPOX versus FOLFOX4, then to bevacizumab versus placebo. PFS was the primary endpoint. In this trial, 1,401 patients were randomly assigned, and the median PFS was 9.4 months for patients receiving bevacizumab and 8.0 months for the patients receiving placebo (HR, 0.83; 97.5% confidence interval [CI], 0.72–0.95; P = .0023).[51][Level of evidence: 1iiDiii] Median OS was 21.3 months for patients receiving bevacizumab and 19.9 months for patients receiving placebo (HR, 0.89; 97.5% CI, 0.76–1.03, P = .077). The median PFS (intention-to-treat analysis) was 8.0 months in the pooled CAPOX-containing arms versus 8.5 months in the FOLFOX4-containing arms (HR, 1.04; 97.5% CI, 0.93–1.16), with the upper limit of the 97.5% CI being below the predefined noninferiority margin of 1.23.[51,52] The effect of bevacizumab on OS is likely to be less than what was seen in the original Hurwitz study.

Investigators from the Eastern Cooperative Oncology Group (ECOG) randomly assigned patients who had progressed on 5-FU/LV and irinotecan to either FOLFOX or FOLFOX and bevacizumab. Patients randomly assigned to FOLFOX and bevacizumab experienced a statistically significant improvement in PFS (7.43 months vs. 4.7 months, HR, 0.61; P < .0001) and OS (12.9 months vs. 10.8 months, HR, 0.75; P = .0011).[53][Level of evidence: 1iiA] Based on these two studies, bevacizumab can reasonably be added to either FOLFIRI or FOLFOX for patients undergoing first-line treatment of metastatic colorectal cancer.

There are currently no completed randomized controlled studies evaluating whether continued use of bevacizumab in the second line or third line after progressing on a first-line bevacizumab regimen is worthwhile.

Cetuximab is a partially humanized monoclonal antibody against the epidermal growth factor receptor (EGFR). For patients who have progressed on irinotecan-containing regimens, a randomized phase II study was performed of either cetuximab or irinotecan and cetuximab. The median TTP for patients receiving cetuximab was 1.5 months compared to median TTP of 4.2 months for patients receiving irinotecan and cetuximab.[57][Level of evidence: 3iiiDiv] On the basis of this study, cetuximab was approved for use in patients with metastatic colorectal cancer refractory to 5-FU and irinotecan.

The Crystal Study (EMR 62202-013 [NCT00154102]) randomly assigned 1,198 patients with stage IV colorectal cancer to FOLFIRI with or without cetuximab.[58] The addition of cetuximab was associated with an improved PFS (HR, 0.85; 95% CI, 0.72–0.99, P = .048 by a stratified log rank test), but not OS.[58][Level of Evidence: 1iiDii] Retrospective studies of patients with metastatic colorectal cancer have suggested that responses to anti-epidermal growth factor receptor (EGFR) antibody therapy are confined to patients with tumors that harbor wild types of KRAS (i.e., lack activating mutations at code on 12 or 13 of the KRAS gene). A subset analysis evaluating efficacy vis a vis KRAS status was done in patients enrolled on the Crystal Study. There was a significant interaction for KRAS mutation status and treatment for tumor response (P = .03) but not for PFS (P = .07). Among KRAS wild-type patients, the HR favored the FOLFIRI/cetuximab group (HR, 0.68; 95% CI, 0.50–0.94).

Panitumumab is a fully humanized antibody against the EGFR. In a phase III trial that has not yet been reported, patients with chemotherapy-refractory colorectal cancer were randomly assigned to panitumumab or best supportive care. Patients receiving panitumumab experienced improved OS. Despite the preliminary nature of this study, the FDA approved panitumumab for use in patients with metastatic colorectal cancer refractory to chemotherapy.[60]

In the Panitumumab Randomized Trial in Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy (PRIME [20050203 or NCT00364013]) study, 1,183 patients were randomly assigned to FOLFOX4 with or without panitumumab as first-line therapy for metastatic colorectal cancer.[61] The study was amended to enlarge the sample size to address patients with the KRAS wild-type tumors and patients with mutant KRAS tumors separately. For patients with KRAS wild-type tumors, a statistically significant improvement in PFS was observed in those who received panitumumab-FOLFOX4 compared with those who received only FOLFOX4 (HR, 0.80; 95% CI, 0.66–0.97; P = .02, stratified log-rank test).[61][Level of evidence: 1iiDiii] Median PFS was 9.6 months (95% CI, 9.2 months–11.1 months) for patients who received panitumumab-FOLFOX4 and 8.0 months (95% CI, 7.5 months–9.3 months) for patients who received FOLFOX4. OS was not significantly different between the groups (HR, 0.83; 95% CI, 0.67–1.02; P = .072). For patients with mutant KRAS tumors, there was worse PFS with the addition of panitumumab (HR, 1.29; 95% CI, 1.04–1.62; P = .02, stratified log-rank test). Median PFS was 7.3 months (95% CI, 6.3 months–8.0 months) for panitumumab-FOLFOX4 and 8.8 months (95% CI, 7.7 months–9.4 months) for FOLFOX4 alone.

Similarly, the addition of panitumumab to a regimen of FOLFOX/bevacizumab resulted in a worse PFS and worse toxicity compared to a regimen of FOLFOX/bevacizumab alone in patients not selected for KRAS mutation in metastatic rectal cancer (11.4 months vs. 10.0 months, HR, 1.27; 95% CI, 1.06–1.52).[62][Level of evidence: 1iiDiii]

The Medical Research Council (MRC) (UKM-MRC-COIN-CR10 [NCT00182715] or COIN trial) sought to answer the question of whether adding cetuximab to combination chemotherapy with a fluoropyrimidine and oxaliplatin in first-line treatment for patients with first-line KRAS wild-type tumors was beneficial.[64,65] In addition, the MRC sought to evaluate the effect of intermittent chemotherapy versus continuous chemotherapy. The 1,630 patients were randomly assigned to three treatment groups:

Arm A: fluoropyrimidine/oxaliplatin.

Arm B: fluoropyrimidine/oxaliplatin/cetuximab.

Arm C: intermittent fluoropyrimidine/oxaliplatin.

The comparisons between arms A and B and arms A and C were analyzed and published separately.[64,65]

In patients with KRAS wild-type tumors (arm A, n = 367; arm B, n = 362), OS did not differ between treatment groups (median survival, 17.9 months [interquartile range (IQR) 10.3–29.2] in the control group vs. 17.0 months [IQR, 9.4–30.1] in the cetuximab group; HR, 1.04; 95% CI, 0.87–1.23, P = .67). Similarly, there was no effect on PFS (8.6 months [IQR, 5.0–12.5] in the control group vs. 8.6 months [IQR, 5.1–13.8] in the cetuximab group; HR, 0.96; 0.82–1.12, P = .60).[64,65][Level of evidence: 1iiA] The reasons for lack of benefit in adding cetuximab are unclear. Subset analyses suggest that the use of capecitabine was associated with an inferior outcome, and the use of second-line therapy was less in patients treated with cetuximab.

There was no difference between the continuously treated patients (arm A) and the intermittently treated patients (arm C). Median survival in the intent-to-treat population (n = 815 in both groups) was 15.8 months (IQR, 9.4–26.1) in arm A and 14.4 months (IQR, 8.0–24.7) in arm C (HR, 1.084; 80% CI, 1.008–1.165). In the per-protocol population, which included only those patients who were free from progression at 12 weeks and randomly assigned to continue treatment or go on a chemotherapy holiday (arm A, n = 467; arm C, n = 511), median survival was 19.6 months (IQR, 13.0–28.1) in arm A and 18.0 months (IQR, 12.1–29.3) in arm C (HR, 1.087, 95% CI, 0.986–1.198). The upper limits of CIs for HRs in both analyses were greater than the predeﬁned noninferiority boundary. While intermittent chemotherapy was not deemed noninferior, there appeared to be clinically insignificant differences in patient outcomes.

Liver metastases

Approximately 15% to 25% of colorectal cancer patients will present with liver metastases at diagnosis, and another 25% to 50% will develop metachronous hepatic metastasis following resection of the primary tumor.[66,67,68] Although only a small proportion of patients with liver metastasis are candidates for surgical resection, advances in tumor ablation techniques and in both regional and systemic chemotherapy provide a number of treatment options.

Hepatic metastasis may be considered to be resectable based on the following:[17,21,24,25,26,27]

Limited number of lesions.

Intrahepatic locations of lesions.

Lack of major vascular involvement.

Absent or limited extrahepatic disease.

Sufficient functional hepatic reserve.

For patients with hepatic metastasis considered to be resectable, a negative-margin resection has resulted in 5-year survival rates of 25% to 40% in mostly nonrandomized studies, such as the NCCTG-934653 trial.[17,21,24,25,26,27] Improved surgical techniques and advances in preoperative imaging have allowed for better patient selection for resection.

Patients with hepatic metastases that are deemed unresectable will occasionally become candidates for resection if they have a good response to chemotherapy. These patients have 5-year survival rates similar to patients who initially had resectable disease.[33] Radiofrequency ablation has emerged as a safe technique (2% major morbidity and <1% mortality rate) that may provide long-term tumor control.[69,70,71,72,73,74,75] Radiofrequency ablation and cryosurgical ablation remain options for patients with tumors that cannot be resected and for patients who are not candidates for liver resection.[76,77,78]

Other local ablative techniques that have been used to manage liver metastases include embolization and interstitial radiation therapy.[79,80,81] Patients with limited pulmonary metastasis, and patients with both pulmonary and hepatic metastasis, may also be considered for surgical resection, with 5-year survival possible in highly selected patients.[82,83,84,85]

A second trial preoperatively randomly assigned patients with one to three potentially resectable colorectal hepatic metastases to either no further therapy or postoperative hepatic arterial floxuridine plus systemic 5-FU.[87] Among those randomly assigned patients, 27% were deemed ineligible at the time of surgery, leaving only 75 patients evaluable for recurrence and survival. Although liver recurrence was decreased, median or 4-year survival was not significantly different between the patient groups. Additional studies are required to evaluate this treatment approach and to determine whether more effective systemic combination chemotherapy alone would provide similar results compared to hepatic intra-arterial therapy plus systemic treatment.

Hepatic intra-arterial chemotherapy with floxuridine for liver metastasis has produced higher overall response rates but no consistent improvement in survival when compared with systemic chemotherapy.[16,88,89,90,91,92] Controversy regarding the efficacy of regional chemotherapy was the basis of a large multicenter phase III trial (CALGB-9481) (NCT00002716) of hepatic arterial infusion versus systemic chemotherapy. The use of combination intra-arterial chemotherapy with hepatic radiation therapy, especially employing focal radiation of metastatic lesions, is under evaluation.[93] Several studies show increased local toxic effects with hepatic infusional therapy, including liver function abnormalities and fatal biliary sclerosis.

Locally Recurrent Rectal Cancer

Locally recurrent rectal cancer may be resectable, particularly if an inadequate prior operation was performed. For patients with local recurrence alone following an initial, attempted curative resection, aggressive local therapy with repeat LAR and coloanal anastomosis, APR, or posterior or total pelvic exenteration can lead to long-term disease-free survival.[94,95] The use of induction chemoradiation for previously nonirradiated patients with locally advanced (pelvic side-wall, sacral, and/or adjacent organ involvement) pelvic recurrence may increase resectability and allow for sphincter preservation.[96,97] Intraoperative radiation therapy in patients who received previous external-beam radiation may improve local control in patients with locally recurrent disease, with acceptable morbidity.[3]

The presence of hydronephrosis associated with recurrence appears to be a contraindication to surgery with curative intent.[98] Patients with limited pulmonary metastases and patients with both pulmonary and hepatic metastases may also be considered for surgical resection, with 5-year survival possible in highly selected patients.[82,83,84]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IV rectal cancer and recurrent rectal cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Changes to This Summary (02 / 08 / 2013)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

General Information About Rectal Cancer

Updated statistics with estimated new cases and deaths for 2013 (cited American Cancer Society as reference 1).

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of rectal cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

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be cited with text, or

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The lead reviewers for Rectal Cancer Treatment are:

Russell S. Berman, MD (New York University School of Medicine)

David P. Ryan, MD (Massachusetts General Hospital)

Jennifer Wo, MD (Massachusetts General Hospital)

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